Efficacy and safety of ACC-9358, a new antiarrhythmic agent.
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Aged↗
Biomedical subjects
R L Woosley
Publications and source records attributed to R L Woosley.
Clinical pharmacokinetics of moricizine.
Moricizine is well absorbed after oral administration and undergoes extensive first-pass metabolism. The drug has a large apparent volume of distribution (approximately 4 liters/kg), exhibits extensive plasma protein binding (approximately 95%) and produces at least 30 metabolites. Indirect evidence indicates that some of those metabolites may be pharmacologically active. The elimination half-life of moricizine is 2 to 6 hours, but its duration of antiarrhythmic action is much longer suggesting active metabolites. Moricizine induces its own metabolism with no change in pharmacologic effect. It also induces the metabolism of theophylline and specific pathways of antipyrine. Cimetidine reduces metabolism of moricizine but does not alter its pharmacologic effects. This observation provides further support for the hypothesis that the metabolites of moricizine contribute to the pharmacologic actions during therapy and indicate that plasma level monitoring is not likely to be of value. There are no known clinically significant pharmacokinetic interactions between moricizine and digoxin, warfarin or propranolol. Excessive prolongation of the PR interval has been seen in some patients receiving both digoxin and moricizine, probably due to additive electrophysiologic effects of the 2 drugs.
Anti-Arrhythmia Agents↗
Concentration/response relations for the multiple antiarrhythmic actions of sotalol.
Sotalol, one of the first beta-receptor antagonists synthesized, is a promising investigational agent with remarkable efficacy for treatment of patients with ventricular and supraventricular arrhythmias. Unlike other beta blockers, sotalol also possesses class III antiarrhythmic action, evidenced by prolongation of the myocardial action potential duration. This additional action probably accounts for the greater antiarrhythmic efficacy of sotalol compared with other beta blockers. Sotalol's class III antiarrhythmic action becomes apparent at concentrations higher than those necessary for significant beta-receptor antagonism, both in vitro and in human subjects. In a study correlating dosage and antiarrhythmic response with prolongation of rate-corrected QT (QTc) (a measure of class III action) and the degree of beta-receptor blockade (assessed by the reduction of the maximal exercise-induced heart rate), 11 of 17 patients had an antiarrhythmic response. Eight of these 11 responders had been unresponsive to conventional beta-receptor antagonists. The plasma concentration associated with significant QTc prolongation (2.55 micrograms/ml) was found to be much greater than that associated with 50% reduction in maximal slowing of heart rate (0.8 micrograms/ml). As with other beta-receptor antagonists, the activities of sotalol's 2 stereoisomers differ, with the I-isomer having far more beta-blocking activity. However, both isomers have equal class III antiarrhythmic activity. When increasing doses of the d-isomer of sotalol (50 to 400 mg every 12 hours) were evaluated in patients with chronic ventricular arrhythmias, arrhythmia frequency was suppressed greater than 80% in 3 patients and 50% in 1 patient.(ABSTRACT TRUNCATED AT 250 WORDS)
Arrhythmias, Cardiac↗
New concepts affecting the use of antiarrhythmic agents.
Three underappreciated concepts having an important impact on the use of antiarrhythmic agents having Class I activity are discussed. These are stereochemical influences on antiarrhythmic action, the modulated receptor theory, and pharmacogenetics. The stereoisomers of some antiarrhythmic agents behave differently in terms of their potency, disposition, and antiarrhythmic action. For example, the enantiomers of both tocainide and mexiletine are cleared at different rates, and those of disopyramide have opposite effects on repolarization. The modulated receptor theory suggests that the affinity of antiarrhythmic drugs to bind to a specific receptor on or near the sodium channel depends on whether the sodium channel is open, resting, or inactivated. Study of the interaction between the state of the sodium channel and the differing actions of the antiarrhythmic agents have provided evidence for synergistic drug combinations. Pharmacogenetics relates to the differences observed in drug metabolism among individuals, which can result in variations of two- to fourfold in clearance and plasma concentration in some cases. There is still much to learn about Class I antiarrhythmic agents. These concepts should lead to a better understanding of their actions and increase their utility.
Anti-Arrhythmia Agents↗
CAST: implications for drug development.
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Anti-Arrhythmia Agents↗
A mechanism of D-(+)-sotalol effects on heart rate not related to beta-adrenoceptor antagonism.
1. In order to determine whether the effects of d- or (+)-sotalol on heart rate are mediated by beta-adrenoceptor antagonism or might be due to other actions, we administered (+)-sotalol (400 mg every 12 h), atenolol (50 mg every 12 h) and placebo to eight healthy volunteers in a randomized, double-blind, crossover study. We also studied the affinity of human lymphocyte beta 2-adrenoceptor for (+)-sotalol, (-)-sotalol, and (+/-)-propranolol. 2. Compared with placebo, atenolol significantly reduced resting, standing and peak exercise heart rate whereas (+)-sotalol significantly reduced standing and peak exercise heart rate, but not resting heart rate. Atenolol significantly reduced resting, standing and peak exercise blood pressure while (+)-sotalol had no effect. 3. (+)-sotalol and atenolol both shifted the relationship between isoprenaline dose and heart rate to the right by similar degrees at the dosages tested. 4. (+)-sotalol but not atenolol significantly prolonged QTc interval. The degree of QTc prolongation due to (+)-sotalol, which has been shown to parallel action potential prolongation in the sinus node, correlated significantly with the reduction in peak exercise. heart rate it produced (r = 0.71, n = 8, P less than 0.05). 5. The affinity of the human lymphocyte beta 2-adrenoceptor was approximately 60-fold greater for (-)-sotalol (Ki, 108 +/- 12 nM) than for (+)-sotalol (Ki, 6,410 +/- 1,020 nM), and approximately 20,000-fold greater for (+/-)-propranolol (Ki, 0.33 +/- 0.08 nM) than for (+)-sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Lack of triggered automaticity despite repolarization abnormalities due to bepridil and lidoflazine.
Bepridil and lidoflazine are calcium channel antagonists that also prolong action potential duration, produce QT interval prolongation on the surface ECG, and have been associated with the distinctive form of ventricular tachycardia, torsade de pointes. It has been demonstrated that quinidine, which also prolongs QT interval and induces torsade de pointes, produces early afterdepolarizations and triggered activity in canine Purkinje fibers driven at slow rates. The effects of bepridil (1-10 microM) and of lidoflazine (5-15 microM) on the transmembrane action potential from canine Purkinje fibers were therefore studied. At long cycle lengths, unlike with quinidine, triggered activity arising during phase 3 was rare; phase 3 secondary plateaus (early afterdepolarizations) were, however, common. Arrest of transmembrane potential between -50 and -60 mV during stimulation at long cycle lengths was also frequently observed (7/20 of bepridil and 3/15 of lidoflazine-treated fibers). In preparations with prominent phase 3 secondary plateaus, addition of epinephrine resulted in triggered activity; similarly, epinephrine caused automaticity from a depolarized membrane potential in 8/9 fibers quiescent at -50 to -60 mV. Thus, the calcium channel blocking drugs bepridil and lidoflazine produced striking repolarization changes at slow stimulation rates, but unlike quinidine, triggered activity was rare. The effect of epinephrine on these drug-treated fibers suggests that the slow inward calcium current plays a role in the generation of triggered activity in the presence of prolonged repolarization.
Action Potentials↗
Suppression of ventricular arrhythmias in man by d-propranolol independent of beta-adrenergic receptor blockade.
To investigate the mechanisms of ventricular arrhythmia suppression by propranolol, we determined the antiarrhythmic efficacy of d-propranolol in 10 patients with frequent ventricular ectopic depolarizations (VEDs) and nonsustained ventricular tachycardia. After an initial placebo phase, 40 mg d-propranolol was administered orally every 6 h with dosage increased every 2 d until arrhythmia suppression (greater than or equal to 80% VED reduction), intolerable side effects, or a maximal dosage (1,280 mg/d) was reached. Response was verified by documenting return of arrhythmia during a final placebo phase. Arrhythmia suppression occurred in six patients while two more had partial responses. Effective dosages were 320-1,280 mg/d (mean 920 +/- 360, SD) of d-propranolol with corresponding plasma concentrations of 60-2,280 ng/ml (mean 858 +/- 681). For the entire group, the QTc interval shortened by 4 +/- 4% (P = 0.03). Arrhythmia suppression was accompanied by a reduction in peak heart rate during exercise of 0-29%. To determine whether arrhythmia suppression could be attributed to beta-blockade, racemic propranolol was then administered in dosages producing the same or greater depression of exercise heart rate. In 3/8 patients, arrhythmias were not suppressed by racemic propranolol indicating that d-propranolol was effective via a non-beta-mediated action. By contrast, in 5/8 patients racemic propranolol also suppressed VEDs. We conclude that propranolol suppresses ventricular arrhythmias by both beta- and non-beta-adrenergic receptor-mediated effects.
Action Potentials↗
Relation between ventricular function and antiarrhythmic responses to sotalol.
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Adult↗
Recainam dose titration and pharmacokinetics in patients with resistant arrhythmias.
Recainam, a new antiarrhythmic drug, was evaluated in 20 patients with drug-resistant stable ventricular arrhythmias. Dosage was increased stepwise every 48 to 72 hours until arrhythmia suppression, side effects, or a predetermined maximal dosage occurred. After a pharmacokinetic evaluation, efficacy was confirmed in a double-blind, crossover protocol. One patient had unusable ambulatory ECG data. There were 14 of 19 patients who responded during dose titration; efficacy was confirmed in 11 of 14. The mean effective dosage and trough plasma concentration were 427 mg every 8 hours and 1.83 micrograms/ml, respectively. One patient withdrew because of nausea. Slowing of intraventricular conduction necessitated dosage reduction in two patients. Plasma half-life was 9.4 +/- 4.1 hours, with renal elimination accounting for 62% of oral clearance. However, 66% of the variability in oral drug clearance was the result of nonrenal elimination. Oral recainam at dosages of 300 to 600 mg every 8 hours is effective in some drug-resistant ventricular arrhythmias and is well tolerated.
Administration, Oral↗
Mexiletine and tocainide: a comparison of antiarrhythmic efficacy, adverse effects, and predictive value of lidocaine testing.
Thirty patients received one of the lidocaine analogues--mexiletine or tocainide--orally for treatment of symptomatic ventricular arrhythmias. Crossover to the other analogue was allowed if initial drug treatment was unsuccessful, and the controlled use of other marketed oral antiarrhythmic agents was permitted. After follow-up of 7 +/- 3 months (SD), mexiletine was successful in 5 of 13 patients initially and in 5 of 14 patients who failed to respond to tocainide. Tocainide was successful in 1 of 17 patients initially and in 2 of 7 who did not respond to mexiletine. Combination therapy was used in nearly half of all ultimately successful drug trials. A common cause of drug trial failure for both drugs was the occurrence of adverse effects that frequently appeared well after hospital discharge. Response to lidocaine was a sensitive but nonspecific predictor of clinical outcome with mexiletine or tocainide that helped to identify drug-resistant patients. Finally, although mexiletine provided effective antiarrhythmic therapy more often than tocainide, response to one lidocaine analogue did not predict response to the other.
Adult↗
Pharmacokinetic and pharmacodynamic interaction of N-acetyl procainamide and procainamide in humans.
Procainamide is a sodium channel blocker which prolongs QRS and QTc intervals, yet its major active metabolite, N-acetylprocainamide (NAPA), generally prolongs only QTc and has very different electrophysiologic and antiarrhythmic actions. In greater than 50% of patients receiving chronic treatment with procainamide, plasma concentrations of NAPA exceed those of procainamide. In this study, we examined the hypothesis that NAPA might alter the disposition kinetics or pharmacologic actions of procainamide. Ten patients with frequent ventricular extrasystoles received intravenous (i.v.) infusions of procainamide alone (study day 1), procainamide and NAPA (study day 2), and NAPA alone (study day 3) at least 48 h apart. On study days 1 and 2, procainamide was administered at a constant rate for 4 h. On study days 2 and 3, NAPA was administered as a loading and maintenance infusion designed to reach a target pseudo-equilibrium plasma concentration of 8 micrograms/ml. NAPA increased procainamide elimination half-life (t1/2) from 275 +/- 42 min (mean +/- SD) on day 1 to 340 +/- 74 min on day 2 (p less than 0.01). A significant correlations was noted between the change in procainamide total clearance on day 2 relative to day 1 and the initial procainamide total clearance on day 1 (r = -0.77, p = 0.009). Findings were similar when procainamide fractional urinary excretion was considered (r = -0.89, p = 0.007). NAPA did not alter procainamide-induced QRS prolongation, but potentiated procainamide-induced QTc prolongation. The antiarrhythmic response to procainamide was not significantly altered by NAPA in seven of nine patients. One patient had greater arrhythmia suppression when NAPA and procainamide were combined than when either was administered alone. In one patient, NAPA apparently antagonized procainamide-induced arrhythmia suppression, but this effect was not reproducible. We conclude that accumulation of NAPA during procainamide therapy can alter both procainamide elimination as well as its electrophysiologic actions.
Acecainide↗
Genetically-determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect.
1. Quinidine is a potent inhibitor of the genetically-determined debrisoquine 4-hydroxylation. Oxidation reactions of several other drugs, including the 5-hydroxylation of the new antiarrhythmic drug propafenone, depend on the isozyme responsible for debrisoquine 4-hydroxylation. 2. The effect of quinidine on the debrisoquine phenotype-dependent 5-hydroxylation and the pharmacological activity of propafenone was studied in seven 'extensive' metabolizers and two 'poor' metabolizers of the drug receiving propafenone for the treatment of ventricular arrhythmias. 3. In patients with the extensive metabolizer phenotype, quinidine increased mean steady-state plasma propafenone concentrations more than two fold, from 408 +/- 351 (mean +/- s.d.) to 1096 +/- 644 ng ml-1 (P less than 0.001), decreased 5-hydroxypropafenone concentrations from 242 +/- 196 to 125 +/- 97 ng ml-1 (P less than 0.02) and reduced propafenone oral clearance by 58 +/- 23%. 4. Despite these changes in plasma concentrations, electrocardiographic intervals and arrhythmia frequency were unaltered by quinidine coadministration, indicating that 5-hydroxypropafenone contributes to the pharmacologic effects of propafenone therapy in extensive metabolizers. 5. In contrasts, plasma concentrations of propafenone and 5-hydroxypropafenone remained unchanged in the two patients with the poor metabolizer phenotype. 6. Biotransformation of substrates for the debrisoquine pathway can be markedly perturbed by even low doses of quinidine; interindividual variability in drug interactions may have a genetic component.
Adult↗
Stereoselective disposition and pharmacologic activity of propafenone enantiomers.
Propafenone is an antiarrhythmic drug that produces a variable degree of beta-blockade in humans and is administered as a racemate. To examine the relative contribution of the individual enantiomers to pharmacologic effects seen during treatment with propafenone, we assessed the steady-state plasma concentrations of (+)-S-propafenone and (-)-R-propafenone in seven patients who were on long-term oral therapy, and we evaluated the electrophysiologic and beta-blocking properties of both enantiomers in vitro. The metabolism of propafenone is known to be polymorphic and to cosegregate with that of debrisoquine-4-hydroxylation. Among five patients with the extensive metabolizer phenotype (EM), the ratio of the area under the plasma concentration-time curve of (+)-S-propafenone to (-)-R-propafenone was 1.73 +/- 0.15 (mean +/- SD). In the other two patients, who had the poor metabolizer phenotype (PM), the concentrations of both enantiomers were elevated but the S/R ratios were similar to those seen in patients with EM. In canine cardiac Purkinje fibers, both enantiomers produced similar frequency-dependent depression of maximum upstroke of phase 0. In contrast, the affinity of the human lymphocyte beta 2-adrenoceptor was approximately 100-fold greater for (+)-S-propafenone (Ki, 7.2 +/- 2.9 nM) than for the (-)-R-enantiomer (Ki, 571 +/- 141 nM). We conclude that during long-term oral therapy, propafenone undergoes stereoselective disposition in patients with either EM or PM. beta-Blockade during propafenone therapy is likely related to accumulation of (+)-S-propafenone.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Acute electrophysiologic effects of sodium administration in dogs treated with O-desmethyl encainide.
Conduction slowing is the major in vivo effect of sodium channel blocking drugs. Although this action may promote arrhythmia suppression, apparently paradoxical arrhythmia aggravation does occur. The latter outcome is most frequently seen during treatment with the class IC agents such as encainide or flecainide, which are potent depressors of conduction even at usual plasma concentrations and heart rates. Anecdotal reports in patients with such drug toxicity have suggested a beneficial effect of sodium lactate or NaHCO3 administration. The purpose of this study, therefore, was to examine the changes induced by sodium loading on the electrophysiologic properties of the canine ventricle pretreated with a class IC drug. Thirty dogs received loading and maintenance infusions of O-desmethyl encainide (ODE), an encainide metabolite that as a sodium channel blocker is approximately 10 times more potent than the parent drug. Interventions were administered during the maintenance phase when stable plasma ODE concentrations of 448 +/- 68 (SEM) ng/ml were present, and QRS was prolonged from 62 +/- 1 to 89 +/- 2 msec, and HV was prolonged from 28 +/- 1 to 50 +/- 1 msec. NaHCO3 (5 meq/kg during 1 minute) shortened QRS from 92 +/- 6 to 76 +/- 3 msec and shortened HV from 44 +/- 3 to 37 +/- 3 msec within 10 minutes (both p less than 0.01). NaHCO3 also significantly prolonged endocardial monophasic action potential duration from 231 +/- 22 to 272 +/- 33 msec and decreased serum [K+] from 3.8 +/- 0.2 to 3.0 +/- 0.2 meq/l, but it did not alter plasma ODE concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
Alkalosis, Respiratory↗
Antiarrhythmic efficacy, clinical electrophysiology, and pharmacokinetics of 3-methoxy-O-desmethyl encainide (MODE) in patients with inducible ventricular tachycardia or fibrillation.
In most patients, the clinical effects of therapy with encainide are mediated by the generation of the active metabolites O-desmethyl encainide and 3-methoxy-O-desmethyl encainide (MODE). Data from in vitro and animal studies have indicated that MODE has electrophysiologic and pharmacokinetic features that make its further evaluation desirable; in earlier studies, we found that MODE suppressed chronic high-frequency nonsustained ventricular arrhythmias at plasma concentrations of 50-160 ng/ml. We now report the clinical electrophysiology, antiarrhythmic activity, and pharmacokinetics of MODE in 17 patients with inducible ventricular tachyarrhythmias (VTs) in whom programmed electrical stimulation was performed before drug administration and after one or two sequences of loading and maintenance infusions of MODE. Because the relation between plasma concentration and effect had been incompletely defined, a dose-titration approach was adopted: available pharmacokinetic data were used to construct loading and maintenance infusion regimens that were predicted to attain low plasma concentrations in initial patients while higher infusion rates were evaluated in subsequent patients. MODE prevented VT induction in three of 17 patients and VT cycle length was increased by greater than or equal to 100 msec in a further seven of 17; most responses to MODE occurred at plasma concentrations greater than 556 ng/ml (greater than 1 SD above mean plasma MODE during encainide therapy). Response to MODE did not predict subsequent response to oral therapy with encainide. MODE increased intracardiac conduction times, QT intervals during atrial and ventricular pacing, and right ventricular effective refractory periods (RVERP); changes in RVERP were most prominent at rapid pacing rates, while changes in intracardiac conduction were rate-independent at cycle lengths between 400 and 600 msec. Plasma MODE concentrations measured during electrophysiology study correlated well with those predicted by the pharmacokinetic simulations (r = 0.91, p less than 0.001). Serial plasma sampling after programmed electrical stimulation indicated a minimum MODE elimination half-life of 8.2 +/- 5.4 hours. Side effects were confined to three instances of asymptomatic conduction system depression in subjects with latent conduction system disturbances. We conclude that MODE slows intracardiac conduction, delays repolarization, and can suppress or substantially modify inducible VT. Moreover, it was only with the adoption of the dose-titration strategy that we were able to safely demonstrate that plasma MODE concentrations higher than those routinely observed during encainide therapy were required to substantially alter cardiac electrophysiology.
Adult↗
Effect of low dose quinidine on encainide pharmacokinetics and pharmacodynamics. Influence of genetic polymorphism.
Encainide biotransformation to its active metabolites O-desmethyl encainide and 3-methoxy-O-desmethyl encainide cosegregates with the polymorphic oxidation of debrisoquine. Because quinidine has been reported recently to be a potent inhibitor of the enzyme responsible for this polymorphism (cytochrome P450db1), we tested the hypothesis that quinidine would selectively inhibit encainide metabolism and alter its effects in subjects with the extensive metabolism phenotype for debrisoquine oxidation. Seven subjects with the extensive and four subjects with the poor metabolism phenotype received encainide (60 mg p.o. and 4.5 mg of [14C]encainide i.v. administered simultaneously) alone and during chronic treatment with low dose quinidine (50 mg q 6 hr) in a randomized, crossover design. In extensive metabolizers, quinidine decreased encainide systemic clearance from 935 +/- 541 to 190 +/- 77 ml/min and encainide nonrenal clearance from 782 +/- 474 to 95 +/- 32 ml/min (both P less than .02). In this population, quinidine significantly increased encainide elimination half-life from 1.8 +/- 1.2 to 7.7 +/- 2.4 hr and fractional urinary recovery of unchanged encainide from 17.5 +/- 7.6 to 47.4 +/- 7.8% (both P less than .001). The extent to which quinidine altered these indices of encainide disposition was highly correlated with the metabolic ratio for debrisoquine oxidation (r = 0.62-0.95). Moreover, poor metabolism and QRS prolongation during encainide were blunted by addition of quinidine; the extent of quinidine-induced reversal of encainide-related ECG changes was also correlated with debrisoquine ratio (r = 0.91). In contrast, in poor metabolizers, quinidine did not change encainide disposition kinetics and neither encainide alone nor encainide plus quinidine significantly altered electrocardiographic intervals.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Role of plasma concentration monitoring in the evaluation of response to antiarrhythmic drugs.
Plasma concentration monitoring of antiarrhythmic agents is valuable, but it is often misused or overemphasized in therapeutic decision-making. There are strict requirements for its appropriate use that are often not met--for both the newer and even the conventional antiarrhythmic drugs. For maximum value, there must be a reliable, accurate relation between the plasma drug concentration and drug action, a relation closer than that between dosage and drug action. The time of sample collection is important--most guidelines are based on "trough" plasma concentrations measured after steady-state equilibrium has been achieved. The use of an accurate, sensitive and specific assay is crucial to the value of plasma concentration monitoring guidelines. However, for agents having active metabolites, monitoring the concentration of only the parent drug can be misleading and limits (but does not necessarily eliminate) the value of plasma concentration monitoring guidelines for these agents. Plasma concentration monitoring of most antiarrhythmic agents is of value for certain specific purposes: to determine compliance to antiarrhythmic therapy, to detect and analyze possible drug interactions, to assess the benefit to risk ratio for increasing the dose of a particular antiarrhythmic agent, to maintain a stable drug effect in the presence of a patient's changing clinical condition and, to a limited extent, to assess the role of an agent in causing an adverse drug reaction. The importance of understanding the assay methods currently in use, as well as how plasma concentration monitoring of individual antiarrhythmic agents is affected by the presence of active metabolites, optical isomers differing in their activity and variations in protein binding, is essential in interpreting data obtained from plasma concentration monitoring.
Anti-Arrhythmia Agents↗